Epoxomicin is a naturally occurring, microbial natural product that is a selective proteasome inhibitor with anti-inflammatory activity. Epoxomicin and analogues and their synthetic derivatives are shown in FIG. 1. Carfilzomib (7), a tetrapeptide epoxyketone, is currently in phase HI clinical trials for multiple myeloma.
Proteasome inhibitors also include structures as shown in FIG. 2, including salinoporamide A (8) and bortezomib (9). Compound 8 is currently in phase I clinical trial for multiple myeloma; compound 9 (marketed as VELCADE™, Millenium Pharmaceuticals) is the first therapeutic proteasome inhibitor to be approved in the U.S. for treating relapsed multiple myeloma and mantle cell lymphoma.
Proteosome inhibitors block the degradation of unneeded or damaged proteins by proteolysis. In addition to anti-cancer activity, proteasome inhibitors have been used to target HIV infection, and have also been shown to have potential in the treatment of autoimmune diseases. For example, proteasome inhibitors have been used to target HIV infection (ritonavir), autoimmune diseases and asthma (lactacystin), and inflammation (epoxomicin).